Study design
Figure 1 depicts the flow of this investigator-initiated, investigator-driven study, which was designed as a single-center, open-label, randomized controlled trial. Patients diagnosed with pulmonary nodules and scheduled to undergo tumor localization before VATS will be randomized (1:1 ratio) to either IOCT or POCT.
Study patients
Subjects aged at least 18 years will be considered eligible for the study if they have a lung tumor requiring localization before VATS. Localization will be deemed necessary when one of the following criteria is met: 1) presence of solid pulmonary nodules of less than 10 mm in size and/or with a distance from the visceral pleura to the edge of nodule of at least 10 mm; or 2) evidence of subpleural cavitary lesions/ground glass nodules (GGNs), independent of their size and/or depth.
Exclusion criteria will be as follows: 1) presence of more than one nodule requiring localization; 2) inability to provide written informed consent; and 3) unwillingness to adhere to the proposed follow-up protocol.
Screening for inclusion
Potentially eligible patients will be approached about potential inclusion either during the prehospitalization visit or while being hospitalized (before scheduled surgery). Complete information about the study objectives will be provided to all candidates.
Randomization
Patients will be randomized to either IOCT or POCT (1:1 ratio) using a computerized randomization tool. We will implement a permuted-block randomization scheme with varying block sizes, while maintaining both allocation and block sizes concealed to the study investigators. Owing to the obvious procedural differences between IOCT and POCT, blinding of surgeons and patients cannot be achieved. In order to ensure an objective evaluation of the endpoints, all of the study outcomes will be investigated by an independent assessor (blinded to the allocation of patients to either POCT or IOCT) through a careful review of clinical records. After randomization, patients will be excluded when tumor regression or progression will be evident on prelocalization images (ultimately abrogating the need of localization). Patients will be allowed to exit from the study at any time.
POCT-guided localization
All POCT-guided localization will be performed on a CT scanner (GE BrightSpeed; GE Healthcare, Milwaukee, WI, USA; Fig. 2a) by a single team of interventional radiologists according to a previously described workflow [8]. Before implementing the procedure, case images will be reviewed to determine the most suitable needle trajectory. Sterile wraps will be positioned around the patient’s chest, followed by injection of 1% lidocaine at the site of needle insertion in the chest. A scalpel will be subsequently used to create a small skin incision followed by the insertion through the chest wall of a 10.7-cm-long, 20-gauge cannula needle containing a double-thorn hookwire (length 20 cm; DuaLok®, Bard Peripheral Vascular Inc., Tempe, AZ, USA). Under intermittent CT guidance, the needle will be positioned at the edge of the nodule of interest. As soon as the needle tip is close to or reaches the lesion, the hookwire will be advanced through the cannula. PBV dye (0.5 mL, patent blue V 2.5%; Guerbet, Aulnay-sous-Bois, France) injected through a 22-gauge, 8.9-long spinal needle will be used to localize superficial lesions (Fig. 2b). The proper reciprocal positioning of the lesion and hookwire will be investigated through an immediate follow-up CT scan. Upon completion of localization, patients will be moved to a general ward before undergoing the scheduled resection.
IOCT-guided localization
Patients in the IOCT group will undergo lesion localization in a hybrid OR equipped with C-arm cone-beam computed tomography (CBCT; ARTIS zeego; Siemens Healthcare GmbH, Erlangen, Germany) and a Magnus surgical table (Maquet Medical Systems, Wayne, NJ, USA) (Fig. 3a). The nodules will be localized and subsequently removed in a unique section by a single team of thoracic surgeons according to a previously described workflow [19]. After induction of general anesthesia, patients will be positioned in the lateral decubitus. A 6-s protocol (6 s DynaCT Body) will be used to acquire an initial scan for surgical planning (with the patient under end-inspiratory breathhold). We will model the needle entry path in the isotropic data set under the syngo Needle Guidance provided with the syngo X-Workplace (Siemens Healthcare GmbH). The needle trajectory will be initially identified by marking the entry and target points. A laser-target cross will be projected onto the patient’s surface to visualize the needle entry point and angulation. An 18-gauge marker needle will be deployed into the patient’s thorax during end-inspiratory breathhold under three-dimensional laser guidance and guided fluoroscopy (Fig. 3b). CBCT will be used to confirm an appropriate needle positioning, and the lesion will be subsequently localized using either a hookwire (DuaLok®; Bard Peripheral Vascular Inc.) or a microcoil (Cook Medical, Bloomington, IN, USA). Superficial lesions will be identified through the injection of either PBV (0.3–0.5 mL, patent blue V 2.5%; Guerbet, Villepinte, France) or near-infrared dye as previously described [20].The correct lesion localization will be confirmed through a post-procedural CBCT scan.
Surgical treatment
Patients in both arms will undergo VATS wedge resection, with the resected specimen being submitted to frozen section examination. Cases with a confirmed diagnosis of primary lung cancer will undergo lobectomy. Patients unable to tolerate lobectomy because of an inadequate pulmonary function or with peripheral lung cancer of limited size (< 2 cm) and adequate resection margins (either > 2 cm or bigger than tumor size) will be treated with a sublobar resection (wedge resection or segmentectomy).
Data collection and management
Each participant will be unequivocally identified through a personal code (accessible to the principal investigator and the study coordinators only) assigned at inclusion. Digital case record forms (CRF) compliant with good clinical practice standards will be used for data collection and managed by the study coordinators and/or research nurses. Paper records will be stored in secured cabinets located at the data coordinating centers, with access being granted to the principal investigator and other researchers (nurses and physicians). Request for consultation of raw data (upon completion of the study) should be directed to the principal investigation. In order to ensure that the primary and secondary study outcomes will be accurately reported, all CRFs will be thoroughly cross-checked with the original sources. Clinical data will be stored in an anonymized fashion in keeping with local privacy laws.
Primary outcome measure
The time required for lesion localization will be the primary outcome measure. In the POCT group, it will be defined as the time elapsed from the beginning of preprocedural CT imaging to the end of postprocedural CT scan. In the IOCT group, it will be calculated from the docking of the C-arm to the end of the procedure (i.e., retraction of the C-arm from the table to the park position).
Secondary endpoints
The following secondary endpoints will be examined: 1) successful targeting rates during localization (defined as the number of successful targeting procedures divided by the number of all localization procedures); 2) successful targeting rates in the operating field (defined as the number of successful targeting procedures minus the number of wire dislodgements or dye fading/spillage occurring in the operation field divided by the number of all localization procedures); 3) time at risk (defined as the time elapsed between the completion of localization and skin incision); 4) other time parameters (including operating time, length of time under anesthesia, global operation room utilization time, and length of hospital stay); 5) rate of conversion to thoracotomy; and 6) complication rates. The occurrence of complications (including pneumothorax and lung hemorrhage) will be recorded after the initial follow-up CT scan following localization. According to the 2010 British Thoracic Society guidelines, large or small pneumothorax will be defined by a distance between the lung margin and chest wall greater or less than 2 cm, respectively [21]. As far as radiation doses are concerned, we will quantify the radiation dose delivered to patients by determining the effective dose (ED). During POCT procedures, the radiation dose delivered by MDCT will be determined using the dose length product (DLP) and expressed as mGy/cm. The radiation dose will be converted to the ED using a suitable conversion factor (0.014, mSvGy− 1 cm− 1) [22]. During IOCT procedures, the radiation doses delivered by both CBCT and fluoroscopy will be determined using the dose area product (DAP) and expressed as mGy/cm2. Two appropriate conversion factors (0.146 and 0.12 mSvGy− 1 cm− 2) will be used to calculate the ED for CBCT and fluoroscopy, respectively [23, 24]. Four sets of thermoluminescent dosimeters (TLDs; UD-802A; Panasonic, Osaka, Japan) will be also placed around the patient’s chest wall (in proximity to the lesion of interest). The radiation dose absorbed by each TLD will be measured using a TLD reader (UD-716AGL TLD reader; Panasonic, Tokyo, Japan) and mean values will be used for analysis.
Follow-up schedule
The start of the study will be set at randomization. Follow-up will be performed until 3 months after surgery according to a predetermined schedule (Fig. 4). Within one week of the operation, we will assess the primary study endpoint. The following variables will be collected: postoperative complications, readmission rates, and deaths occurring within 30 and 90 postoperative days. Postoperative visits will be scheduled at 3–4 weeks after surgery and at 3 postoperative months.
Sample size calculation
The sample size was established according to a retrospective study previously designed by our group [25]. Our original assumption was that the time required for tumor localization would be the same in the IOCT and POCT groups. Based on a two-sample t-test under an equality hypothesis, at least 24 patients per treatment arm will be required under the following conditions: alpha error, 0.05; power, 80%; and a balanced trial design. Under the assumption of a 10% total dropout rate, we are planning to enroll at least 27 patients in each arm.
Timeline
The clinical trial will last two years, a time span that includes prearrangement and statistical analysis. Recruitment began on October 8, 2018, with a planned 2-year duration. Data analysis is scheduled to start upon discharge of the last randomized patient.
Data analysis
Both intention-to-treat (i.e., in all of the randomized patients) and per-protocol (i.e., only in patients who will have their pulmonary lesion localized according to the method assigned on randomization and with complete follow-up data) analyses will be conducted. Categorical variables will be expressed as frequencies and compared with the chi-squared test or the Fisher’s exact test, as appropriate. Continuous data will be summarized as means ± standard deviations (for Gaussian variables) or medians and interquartile ranges (for skewed parameters). The Mann-Whitney U test and the Student’s t-test will be used to compare normally distributed and skewed continuous variables, respectively. Two software packages—SAS (version 9.3; SAS Institute Inc., Cary, NC, USA) and SPSS (version 20.0; SPSS Inc., Chicago, IL, USA)—will be used for statistical calculations. A P value < 0.05 (two-tailed) will be considered statistically significant.